2. Academic Validation
  3. ENPP1 blockade with a humanized monoclonal antibody enhances renal repair after acute kidney injury

ENPP1 blockade with a humanized monoclonal antibody enhances renal repair after acute kidney injury

  • Cell Stem Cell. 2026 Jul 2;33(7):1110-1126.e7. doi: 10.1016/j.stem.2026.05.011.
Lianjiu Su 1,  Qihao Sun 1,  Ziheng Zhou 1,  Rending Wang 2,  Junqiang Wang 3,  Juan Felipe Alvarez 1,  Bo Tao 1,  Kiran Das 1,  Qiuyuan Zhou 4,  Jing Wang 5,  Guanglin Zhang 6,  Johanna Ten Hoeve 7,  Linlin Zhang 1,  Calvin Pan 8,  Qiang Du 5,  Hooman Allayee 9,  Zhihao Liu 1,  Ilya Savchenko 1,  Shan Kou 10,  Jijun Wan 1,  Matteo Pellegrini 11,  Aldons J Lusis 12,  Thomas Graeber 13,  Shen Li 1,  Arjun Deb 14
Affiliations

Affiliations

  • 1 Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 2 Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
  • 3 Department of Ophthalmology and Stein Eye Institute, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA.
  • 4 Department of Pathology, Liang Ping People's Hospital of Chongqing, Chongqing 404200, China.
  • 5 Department of Pathology, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
  • 6 Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 7 UCLA Metabolomics Center, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 8 Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA.
  • 9 Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 10 Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 11 Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 12 Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 13 UCLA Metabolomics Center, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 14 Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].
PMID: 42302792 DOI: 10.1016/j.stem.2026.05.011
Abstract

The kidney possesses a poor ability to robustly regenerate and repair after acute injury. We show that the ectonucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase-1) is robustly expressed in diseased human kidneys and strongly correlates with clinical indices of renal dysfunction. Genetic targeting of Enpp1 in mice enhanced renal repair. A humanized monoclonal antibody, targeting human ENPP1 (hENPP1mAb), when administered in humanized mice, led to tubular cell proliferation, enhanced renal glomerular filtration rate, decreased fibrosis, and rescued renal function after kidney injury. hENPP1mAb augmented nucleotide metabolism and cellular energetics, enabling proliferation and rescuing cell cycle arrest. Single-cell transcriptomics demonstrated expanded signatures of effective repair with hENPP1mAb. In a good laboratory practice (GLP)-compliant dose escalation study, hENPP1mAb was found to be non-toxic and highly tolerated in non-human primates. Our findings identify ENPP1 as a central regulator of acute kidney injury and demonstrate the therapeutic benefit of targeting ENPP1 ectonucleotidase activity with a humanized monoclonal antibody.

Keywords

fibrosis; kidney injury; kidney regeneration; monoclonal antibody.

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